Freeze-drying, also known as lyophilization, is a process for drying high-quality products such as, for example, pharmaceuticals, biological materials such as proteins, enzymes, microorganisms, and in general any thermo- and/or hydrolysis-sensitive materials. Freeze-drying provides for the drying of the target product via sublimation of ice crystals into water vapor, i.e., via the direct transition of at least a portion of the water content of the product from the solid phase into the gas phase. Freeze-drying is normally performed under vacuum (i.e., low pressure) conditions, but works generally also under different pressure conditions, e.g., atmospheric pressure conditions.
Freeze-drying processes in the pharmaceutical area may be employed, for example, for the drying of Active Pharmaceutical Ingredients (“APIs”), drugs, drug formulations, hormones, peptide-based hormones, carbohydrates, monoclonal antibodies, blood plasma products or derivatives thereof, immunological compositions including vaccines, therapeutics, other injectables, and in general substances which otherwise would not be stable over a desired time span. In order for the freeze-dried product to be stored and shipped, the water (or other solvent) has to be removed prior to sealing the product in vials or containers for preserving sterility and/or containment. In the case of pharmaceuticals and biological products, the freeze-dried (lyophilized) product may be reconstituted later by dissolving the product in a suitable reconstituting medium (e.g., pharmaceutical grade diluent) prior to administration, e.g., injection.
A freeze-dryer is generally understood as a process device employed in a process line for the production of freeze-dried particles such as granules or pellets with sizes ranging typically ranging from several micrometer to several millimeters. The process line may be under closed conditions, i.e., under the requirement of protecting sterility of the product, or under the requirement of containment, or both. Production under sterile conditions prevents contaminants from entering into the product. Production under containment means that neither the product, elements thereof, nor any auxiliary or supplementary materials enter the environment.
Implementing a process line to run under closed conditions is a complex task. Therefore a general need exists for design concepts that reduce the complexity of process lines and process devices such as freeze-dryers. Reducing the complexity of the process lines and process devices enables more cost-effective production of pharmaceuticals and/or bio-pharmaceuticals and other high-quality goods.
Various design approaches for constructing freeze-dryers are known. In one example, DE 10 2005 020 561 A1 describes the production of freeze-dried round particles in a drying chamber that includes a fluidized bed. In this device, a process gas with the appropriate temperature flows from below the bed via a bottom screen through the drying chamber. The process gas is dehumidified, such that the process gas absorbs humidity such that it consequentially removes product humidity via sublimation. While the design allows careful drying of round particles with amorphous structure the need for a dehumidified process gas leads to the relatively high costs seen in using this approach.
WO 2006/008006 A1 describes a process for sterile freezing, freeze-drying, storing, and assaying of a pelletized product. The process comprises creating frozen pellets in a freezing tunnel, which are then directed into a drying chamber, wherein the pellets are freeze-dried on a plurality of pellet-carrying surfaces; the pellets are thus dried as bulkware, i.e., before the filling thereof into vials. From the feeding tunnel, the pellets are distributed by feeder channels onto the pellet carriers. Heating plates are arranged below each of the carriers. A vibrator is provided for vibrating the drying chamber during the drying process. Pelletizing and freeze-drying are performed in a sterile volume provided inside an isolator. After freeze-drying, the pellets are unloaded into a storage container. While drying the pellets as bulkware provides for a higher drying efficiency than drying the pellets only after the dispensing them into vials, the other process lines elements of providing a drying chamber with multiple pellet carriers, having a complex arrangements of feeder channels and channels for de-loading the freeze-dryer, heating plates, and vibrating means leads to a complex arrangement that may be difficult to clean/sterilize, as well as having other potential drawbacks. Moreover, keeping the entire process line of droplet generator, freezing tunnel, and freeze-dryer within one isolator further adds to the complexity and costs associated of this design approach.
WO 2009/109550 A1 describes a process for stabilizing an adjuvant containing a vaccine composition in dry form. The process comprises prilling and freezing a formulation, bulk freeze-drying, and then dry dispensing the product into final recipient containers. The freeze-dryer comprises pre-cooled trays, that collect the frozen particles which are then loaded on pre-cooled shelves in the freeze-dryer. Once the freeze-dryer is loaded, a vacuum is pulled in the freeze-drying chamber to initiate sublimation of water vapor from the pellets. In addition to tray-based freeze-drying, a number of techniques, such as atmospheric freeze-drying, fluidized bed drying, vacuum rotary drum drying, stirred freeze-drying, vibrated freeze-drying, and microwave freeze-drying are indicated as being applicable options for the freeze-drying.
DE 196 54 134 C2 describes a device for freeze-drying products in a rotatable drum. The drum is heated and the sublimation vapor released from the product is drawn off the drum. The drum is filled with the bulk product and is slowly rotated in order to achieve a steady heat transfer between product and inner wall of the drum. The inner wall of the drum can be heated by a heating means provided in an annular space between the drum and a chamber housing the drum. Cooling can be achieved by a cryogenic medium inserted into the annular space. It is proposed that the device be used for pharmaceutical or biological materials. However, it is not specifically described how, for example, the sterility of the product is protected or achieved. Following the approach in WO 2006/008006 A1, an isolator would need to be provided for receiving the freeze-drying device of DE 196 54 134 C2 for a production under sterile conditions. This leads to a complex arrangement.